Methods for the preparation of 4-hydroxybenzothiophene have been described by Iwasaki et al. (1991) J. Org. Chem. 1991. 56, 1922. Here a cyclocarbonylation of a primary allylacetate is performed in presence of a high catalyst loading. Further, this process is characterized by at least five process steps which in part require extreme reaction conditions. Therefore, a simpler more efficient process utilizing less process steps has been long desired.
The present invention is concerned with a novel process for the preparation of benzothiophene derivatives, especially with the preparation of 4-hydroxybenzothiophene. 4-Hydroxybenzothiophene is a building block for pharmaceutically active compounds, e.g. 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione. This compound is known in the art and is described for example in International Patent Application WO 94/27995. It is especially useful for prophylaxis and treatment of diabetes mellitus type I and II.
Surprisingly it has been found that using the process according to the present invention 4-hydroxybenzothiophene can be prepared with less process steps under moderate conditions with an outstanding yield.
In accordance with this invention, a new procedure is provided for preparing 4-hydroxybenzothiophene having the formula 
from a compound of 
wherein
Y is halogen or xe2x80x94OR; and
xe2x80x94OR is an aryloxy group or a group of formulae xe2x80x94(CO)xe2x80x94Rxe2x80x2, xe2x80x94Oxe2x80x94(CO)xe2x80x94Oxe2x80x94Rxe2x80x3, or xe2x80x94Oxe2x80x94(PO)xe2x80x94(ORxe2x80x3)2, wherein Rxe2x80x2 is alkyl, perfluoro-C1-20-alkyl, aryl, Rxe2x80x3 is alkyl, aryl or benzyl;
which comprises cyclocarbonylating the compound of formula II by reacting, in an organic solvent medium containing a carboxylic acid anhydride and a base, the compound of formula II with carbon monoxide in the presence of a carbonylation catalyst capable of complexing with carbon monoxide to produce the carboxylic acid ester of the compound of formula I as a reaction product and thereafter saponifying this reaction product to produce the compound of formula I above.
The cyclocarbonylation is carried out by introducing carbon monoxide into the reaction medium containing the compound of formula II above and a carbonylation catalyst capable of complexing with carbon monoxide to produce the carboxylic acid ester of the compound of formula I as a reaction product. The saponification step is carried out after this reaction product is formed. The saponification is carried out by adding a base to the reaction medium so that the pH is raised to any value of from 8 to 14.
Surprisingly, it has been found that using the process of this invention, the 4-hydroxybenzothiophene can be prepared with less process steps under moderate conditions and with an outstanding yield. The process also provides an efficient cyclocarbonylation reaction under mild conditions in a single reaction medium so that the starting material for this reaction, i.e., the compound of formula II, does not have to be purified such as by distillation but can be used as crude material. Therefore, this process provides an efficient cyclocarbonylation reaction under mild conditions. In addition, substrates for the cyclocarbonylation reaction (compound of Formula II) do not need to be purified, e.g. by distillation, but can be used as xe2x80x9ccrudexe2x80x9d material.
According to the present invention, the term xe2x80x9ccyclocarbonylationxe2x80x9d refers to an introduction of a carbonyl group by means of carbon monoxide gas coupled with the formation of a cyclic ring structure.
The term xe2x80x9csaponificationxe2x80x9d refers to the hydrolysis of an ester under basic conditions.
The term xe2x80x9ctransition metal compoundxe2x80x9d refers to a metal-phosphine complex compound wherein the term metal refers to Pd, Pt, Ru, Co, Rh or Ni, preferably Pd.
The term xe2x80x9cligandxe2x80x9d refers to phosphine, arsine or stibine derivatives, preferable phosphine derivatives, of general formulae P(R1)(R2)(R3), (R1)(R2)Pxe2x80x94(X)xe2x80x94P(R1)(R2), As(R1)(R2)(R3) or Sb(R1)(R2)(R3), preferably P(R1)(R2)(R3), wherein R1, R2, and R3 are defined below.
The term xe2x80x9calkylxe2x80x9d refers to a branched or straight chain monovalent alkyl radical of one to nine carbon atoms (unless otherwise indicated), preferably one to four (lower) carbon atoms. This term is further exemplified by such radicals as methyl, ethyl, n-propyl, isopropyl, i-butyl, n-butyl, t-butyl and the like.
The term xe2x80x9carylxe2x80x9d refers to a monovalent carbocyclic aromatic radical, e.g. phenyl, optionally substituted, independently, with halogen, lower-alkyl, lower-alkoxy, lower-alkylenedioxy, carboxy, trifluoromethyl and the like, with phenyl being especially preferred.
The term xe2x80x9clower alkanoic acidxe2x80x9d refers to those lower alkanoic acids containing from 2 to 6 carbon acids such as propionic acid, acetic acid, etc.
The term xe2x80x9caryloxyxe2x80x9d, signifies a group of the formula aryl-Oxe2x80x94 in which the term xe2x80x9carylxe2x80x9d has the significance given above. Phenyloxy is a preferred example of such an aryloxy group.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, signifies a group of the formula alkyl-Oxe2x80x94 in which the term xe2x80x9calkylxe2x80x9d has the significance given above, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec.butoxy and tertbutoxy, preferably methoxy and ethoxy.
The term xe2x80x9calkylenedioxyxe2x80x9d refers to C1-3-alkyl-dioxy groups, such as methylenedioxy, ethylenedioxy or propylenedioxy.
The term xe2x80x9chalogenxe2x80x9d refers to fluorine, chlorine, and bromine.
In more detail, the present invention refers to a process for the preparation of compounds of formula I 
comprising cyclocarbonylation of a compound of formula II 
wherein
Y is halogen or xe2x80x94OR;
xe2x80x94OR is an aryloxy group or a group of formulae xe2x80x94Oxe2x80x94(CO)xe2x80x94Rxe2x80x2, xe2x80x94Oxe2x80x94(CO)xe2x80x94Oxe2x80x94Rxe2x80x3 or xe2x80x94Oxe2x80x94(PO)xe2x80x94(ORxe2x80x3)2, wherein Rxe2x80x2 is alkyl, perfluoro-C1-20-alkyl, aryl, Rxe2x80x3 is alkyl, aryl or benzyl;
followed by saponification.
In a preferred embodiment of the invention, the cyclocarbonylation reaction is carried out in the presence of a base and the carbonylation catalyst is a complex of a transition metal compound with a ligand.
In a preferred embodiment of this invention, the cyclocarbonylation reaction carried out in the presence of a base and a carboxylic acid anhydride, one utilizes a catalyst which is a transition metal compound complexed with a ligand. Cyclocarbonylation reactions and their conditions are known. Any of the conventional conditions utilized in such cyclocarbonylation reactions can be utilized in accordance with the process of this invention.
In accordance with the process of this invention, this cyclocarbonylation reaction is carried out in the presence of a carbonylation catalyst capable of complexing with carbon monoxide. Any conventional carbonylation catalyst capable of complexing with carbon monoxide can be utilized in accordance with this invention. Among the preferred catalysts are those catalysts which are transition metal compounds complexed with a ligand. Transition metal compounds useful for the process of the present invention comprise salts of Pd, Pt, Ru, Co, Rhxe2x80x94 or Ni and also include transition metals on an inert support such as Pd/C. The use of transition metal compounds as catalysts has been described for example in Matsuzaka et al. (1988) J. Org. Chem. 53, 3832. Preferred transition metal compounds are salts of palladium, e.g. Pd(OAc)2, Pd2dba3, PdCl2, Pd2Cl2(xcfx80-allyl)2, PdCl2(NCMe)2, [PD(NCMe)4](BF4)2, and most preferably Pd(OAc)2. The mentioned catalysts are known in the art (e.g. U.S. Pat. No. 5,380,861; xe2x80x9cCarbonylation, Direct Synthesis of Carbonyl Compoundsxe2x80x9d, H. M. Colquhoun, D. J. Thompson, M. V. Trigg, Plenum Press, 1991) and/or are commercially available (e.g. from Fluka, Buchs, Switzerland or Strem Chemicals, Kehl, Germany).
The ligand of the transition metal compound in the catalyst may be selected from a group consisting of phosphine, arsine or stibine derivatives, preferable phosphine derivatives of general formulae P(R1)(R2)(R3), (R1)(R2)Pxe2x80x94(X)xe2x80x94P(R1)(R2), As(R1)(R2)(R3) or Sb(R1)(R2)(R3), preferably P(R1)(R2)(R3), wherein X, R1, R2, and R3 are defined below.
Especially suitable ligands are chiral and non-chiral mono- and diphosphorus compounds for example described in Houben-Weyl, xe2x80x9cMethoden der organischen Chemiexe2x80x9d, vol. E1, page 106 et seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4, 145-202 (1981), especially those of the formulae
P(R1)(R2)(R3) and (R1)(R2)Pxe2x80x94(X)xe2x80x94P(R1)(R2)
wherein R1, R2 and R3 each independently are C1-8-alkyl, cyclohexyl, benzyl, naphthyl, 2- or 3-pyrrolyl, 2- or 3-furyl, 2- or 3-thiophenyl, 2- or 3- or 4-pyridyl, phenyl or phenyl which is substituted by C1-4-alkyl, C1-4-alkoxy, halogen, trifluoromethyl, lower alkylydenedioxy or phenyl and X is binaphthyl, 6,6xe2x80x2-dimethyl- or 6,6xe2x80x2-dimethoxybiphenyl-2,2xe2x80x2-diyl, or one of the groups xe2x80x94(CH2)nxe2x80x94, xe2x80x94CH2CH2xe2x80x94P(C6H5)xe2x80x94CH2CH2xe2x80x94, 
and n is a number of 1-8.
Examples of suitable phosphorus ligands are shown in Scheme 1. 
The most preferred phosphorus ligands are triphenylphosphine, 
The preparation of a transition metal complex is explained in more detail for the corresponding palladium-phosphine complex: The palladium-phosphine complex compound is conveniently formed in situ from a palladium component and a phosphine ligand. These palladium components is for example metallic palladium, which is optionally supported on a carrier material such as carbon, or a complex or a salt of 0-, 2- or 4-valent palladium such as palladium-bis(dibenzylideneacetone), palladium chloride, palladium acetate and the like. For the in situ preparation, the phosphorus ligand/transition metal compound ratio (mol/mol; P/Pd) amounts to about 0.1:1 to 100:1, preferably to about 6:1 to 15:1. Suitable phosphine ligands are for example chiral and non-chiral mono- and diphosphorus compounds such as are described in Houben-Weyl, Methoden der organischen Chemie, volume E1, page 106 et. seq. Georg Thieme Verlag Stuttgart, 1982, and Aspects Homog. Catal., 4, 145-202 (1981), especially those described above.
For the in situ preparation of the palladium-phosphine complex compound palladium-(II) chloride or palladium-(II) acetate, palladium-dichloro-bis(acetonitrile) and a bis(diphenylphosphino)alkane maybe used.
Further, the process of the present invention comprises the use of bases for the cyclocarbonylation reaction like tertiary bases such as tri-alkyl-amines, di-alkyl-aryl-amines, pyridines, alkyl-N-piperidines, and for example inorganic bases such as NaOH, KOH or salts of carbonic acids. Examples are (alkyl)3amines, e.g. triethylamine, ethyl-di-isopropyl-amine, pyridine, N-methyl-piperidine, sodium hydrogen carbonate, potassium hydrogen carbonate, di-sodium carbonate, etc. The preferred base is triethylamine. However, any base conventionally used for cyclocarbonylation can be used in the process of this invention.
Any conventional inert solvent can be used as the reaction medium. Solvents for the above reaction are known to skilled persons. Preferred solvents are aromatic solvents, e.g. toluene, xylene, benzene, halogenated hydrocarbons, e.g. CH2Cl2, nitrites, e.g. acetonitrile, ester, e.g. ethylacetate, amides, e.g. DMF, ether, e.g. THF, dioxane, urethanes, e.g. TMU, sulfoxides, e.g. DMSO, and mixtures thereof The preferred solvent is toluene.
In carrying out the cyclocarbonylation reaction any of the conditions conventionally employed in carrying out such reaction can be utilized in accordance with this invention. This reaction is carried out so that one mole of carbon monoxide is reacted with one mole of the compound of formula II to produce the cyclocarbonylated reaction product which reaction product is the carboxylic acid ester of the compound of formula I. This reaction is carried out by introducing carbon monoxide into the reaction medium. In carrying out this reaction, usually a stoichiometric excess of carbon monoxide is added to the reaction medium to ensure complete reaction. This is achieved by adjusting the pressure of the carbon monoxide added. By utilizing the conventional reaction conditions for such cyclocarbonylation reaction, one achieves the formation of the reaction product of one mole of the carbon monoxide with one mole of the compound of formula II above. The reaction product formed from this reaction is not isolated from the reaction medium but is treated with a base to remove the ester group from the hydroxy moiety on the compound of formula I and form the compound of formula I. In the cyclocarbonylation reaction, the temperature can vary between 40xc2x0 C. and 170xc2x0 C., preferably between 60-120xc2x0 C., and most preferably the reaction is performed at about 90xc2x0 C. The substrate/catalyst ratio (mol/mol; S/Pd) amounts to 1 to 10000, preferably 100 to 5000, more preferably 1000 to 2000 and most preferably 1200 to 1500. For the in situ preparation, the above mentioned phosphorus ligand/transition metal compound ratio (mol/mol; P/Pd) amounts to 0.1:1 to 100:1, preferably 6:1 to 15:1. The upper limit for the carbon monoxide (CO) pressure is only limited by the specification of the autoclave used. For the lower pressure limit the carbonylation reaction would work even with a CO pressure of 1 bar. Preferably, the CO pressure is about 20 to 70 bar, more preferably 35 to 60 bar.
The cyclocarbonylation reaction of this invention is carried out in the presence of a base and a carboxylic acid anhydride to form the carboxylic acid ester of the compound of formula I. Any conventional carboxylic acid anhydride can be used, particularly the aroic acid anhydrides and the lower alkanoic acid anhydrides. Among the preferred carboxylic acid anhydrides are benzoic acid anhydride and acetic acid anhydride with acetic acid anhydride being particularly preferred. The carboxylic acid anhydride should be present in the reaction medium in sufficient quantity to allow it to react, during the cyclocarbonylation reaction, with all of the compounds of formula II present in this reaction medium. However, a stoichiometric excess of the carboxylic acid anhydride can be present in the reaction medium.
Surprisingly it has been found that the xe2x80x9ccrudexe2x80x9d compound of Formula II can be used for the preparation of the compound of Formula I. A preparation of a crude material is performed by collecting the compound of Formula II, e.g. 1-(2-thienyl)allyl acetate, with an organic solvent and drying without further purification. The preparation of this material is exemplified in Example 1. Example 2 B shows the use of the crude starting material for the preparation of the compound of Formula I.
The cyclocarbonylation reaction is followed by saponification. Conditions for saponification reactions are known in the art and described for example in xe2x80x9cPractical Organic Chemistryxe2x80x9d, A. I. Vogel, Longmans Ed., 1967, p. 390-393. In carrying the saponification reaction of the carboxylation acid ester of formula I, the reaction medium in which this reaction product is formed is treated with a base. Any conventional base can be utilized. Normally, it is preferred to utilize the alkali metal or alkaline earth metal bases such as alkali metal, hydroxides, alkoxides, etc. In a preferred embodiment of the present invention, the saponification is carried out in a biphasic mixture of aqueous sodium hydroxide and toluene or in an homogeneous mixture of sodium methylate in methanol.
Compounds of Formula II may be prepared by methods known in the art, for example by reaction of a thiophene carbaldehyde of Formula III (illustrated in Scheme 2 a; commercially available, Fluka, Aldrich). 
with a vinyl-metal-X reagent, with -metal-X being xe2x80x94MgCl, xe2x80x94MgBr, xe2x80x94MgI or xe2x80x94Li, preferably xe2x80x94MgCl or xe2x80x94MgBr, followed by reaction with an acid derivative. Other allyl compounds, e.g. the corresponding allyl halogenides or allyl trialkylammonium salts, are also suitable reagents. The acid derivative can be selected from a group consisting of compounds of formulae, (Rxe2x80x2xe2x80x94CO)2O, Rxe2x80x3Oxe2x80x94(CO)xe2x80x94Cl, Clxe2x80x94(PO)(ORxe2x80x3)2, Rxe2x80x2xe2x80x94(CO)-Hal wherein Rxe2x80x2 is alky, perfluoro-C1-20-alkyl, aryl, Rxe2x80x3 is alkyl, aryl or benzyl and Hal is Cl or Br. The preferred acid derivative is (Rxe2x80x2xe2x80x94CO)2O, and here especially the acetanhydride. The most preferred the vinyl-metal-X-reagents are vinylmagnesium chloride or vinylmagnesium bromide.
In the most preferred embodiment of the present invention, the compound of Formula II is prepared by reaction of vinylmagnesium chloride followed by reaction with acetanhydride as shown in scheme 2, variant a).
Additional methods for the preparation of compound III are summarized in scheme 2.
The compound of Formula I is usefull for the preparation of pharmaceutically active substances, e.g. 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione and its salts, especially the corresponding sodium salt. A process for the preparation of this compound has been described for example in International Patent Application WO 98/42704.
In addition, the compounds may be prepared according to the following processes:
In a first step the compound of Formula I may be converted into 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole by reaction with a mesylate of Formula V 
under basic conditions. The reaction may be performed in solvents like DMF with for example sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium carbonate; or in THF with KtBu; or in toluene and KOH with phase transfer catalysts.
The above process may be followed by a nitration reaction of 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole. Normally nitric acid is used for the nitration reaction which may be performed at room temperature to about 50xc2x0 C., preferably room temperature.
The 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole obtained by the above process may be converted into of 5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole by hydrogenation. The conditions of the hydrogenation reaction (H2/Raney nickel) are known in the art. Hydrogen pressure may be 1 to 10 bar, preferably 1 bar.
The above process may be continued by the reaction of 5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole with HHal/NaNO2 followed by reaction with CHxe2x95x90CHCOOCH3/Cu(I)Hal, wherein Hal is Br or Cl, preferably Br. The reaction product in case of Hal is Br is methyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate.
The reaction of methyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate with thiourea will produce 2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one. The reaction is normally performed in alkylalkohols like ethanol.
This compound (2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one) may then be converted into 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione by reaction under acid conditions. The reaction maybe performed at 1-4 bar, preferably at 1 bar. Acidic conditions are provided by an organic or inorganic add in an appropriate solvent, e.g. HCl/ethanol.
The reaction maybe optionally continued by conversion of 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-6l)-ethoxy]-enzothiophene-7-methyl]-2,4-thiazolidinedione in a corresponding salt, preferably the sodium salt (5-[4-[2-(5-ethyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione by reaction under basic conditions, preferably with NaOH in THF.
A further embodiment of the invention comprises a process for the preparation of 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione and/or of 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiphene-7-methyl]-2,4-thiazolidinedione sodium salt comprising
a) conversion of a compound of Formula I into 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole by reaction of a compound of Formula I 
xe2x80x83with a mesylate of Formula V 
xe2x80x83under basic conditions; followed by
b) nitration of 4-[2-(benzothiophene-4-yloxy)-ethyl]-5-methyl-2-phenyl-oxazole to give 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole;
c) hydrogenation of 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole to give 5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole; followed by
d) reaction of 5-methyl-4-[2-(7-amino-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole with HHal/NaNO2 and CHxe2x95x90CHCOOCH3/Cu(I)Hal, wherein Hal is Br or Cl to give methyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate; followed by
e) reaction of methyl-2-bromo-3-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-propionate with thiourea to give 2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one; followed by
f) reaction of 2-imino-5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-yl]-methyl-thiazolidine-4-one under acid conditions to give 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiopene-7-methyl]-2,4-thiazolidinedione; and
g) optionally followed by reaction of 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione under basic conditions to give 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione.
The invention further comprises the use of any of the above described processes for the preparation of 5-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-7-benzothiophenylmethyl]-2,4-thiazolidinedione and 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione.
A further embodiment of the present invention comprises the compound 5-[4-[2-(5-methyl-2-phenyl-oxazole-4-yl)-ethoxy]-benzothiophene-7-methyl]-2,4-thiazolidinedione.